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CAQ CORNER

Basic Concepts in Transplant Immunology
Olivia M. Martinez1 and Hugo R. Rosen2
he liver is unique among transplanted organs with respect to its complex, and sometimes paradoxical, interaction with the host immune system. Early liver transplantation studies with outbred swine demonstrated that a significant percentage of recipients maintained their graft in the absence of immunosuppression.1 Subsequently, spontaneous liver allograft acceptance was also observed in transplants done in several allogeneic rat strain combinations and most allogeneic mouse strain combinations. Moreover, other experimental studies in rodents demonstrated that allogeneic liver transplantation provides immune “protection” against subsequent cardiac, kidney, pancreas, islet, and skin grafts from the same donor.1-7 Finally, in clinical transplantation there is increasing evidence, both anecdotal and documented, that some liver transplant recipients who cease taking immunosuppressive drugs maintain allograft function, suggesting robust tolerance is in place. Hence, the liver shows features of immune privilege. Nevertheless, the liver can display destructive immunologic processes since acute liver allograft rejection does occur in approximately 50% to 75% of liver transplant recipients, although in the majority of cases it is readily reversed with immunosuppressive approaches tailored to treat cellular rejection (covered in a separate CAQ corner). Whereas immune responses within the liver can effectively eliminate hepatotropic pathogens including hepatitis A, other liver pathogens such as hepatitis C persist and manage to avoid elimination by the immune system. Finally, a variety of autoimmune diseases with unknown
Abbreviations: Th, T helper cell; IL, interleukin; DC, dendritic cell; APCs, antigen-presenting cells; MHC, major histocompatibility complex; LSEC, liver sinusoidal endothelial cell; NK, natural killer; TCR, T-cell receptor; IFN, interferon; CTLA4, cytotoxic T lymphocyte associated antigen 4; Ig, immunoglobulin; ICOS, inducible costimulator; PD, programmed death; PDL, programmed death ligand; CTLs, cytotoxic T lymphocytes; FasL, Fas ligand; HLA, human leukocyte antigen. From the 1Stanford University School of Medicine, Stanford, CA; and 2Oregon Health and Science University / Portland VAMC, Portland, OR. Address reprint requests to Olivia Martinez, PhD, Stanford University School of Medicine, 1201 Welch Road, MSLS P312, Stanford, CA 94305-5492. Telephone: 650-498-6247; FAX: 650-498-6250; E-mail: omm@stanford.edu Copyright © 2005 by the American Association for the Study of Liver Diseases Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/lt.20406

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etiologies target the liver, including primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and biliary atresia. Together, these observations underscore the enigmatic relationship between the liver and host immunity. In this article, we discuss the hepatic immune system, basic principles governing the host T-cell response to alloantigen following liver transplantation, experimental studies elucidating the cellular and molecular mechanisms of liver allograft rejection and tolerance, and immunologic perspectives of recent developments in clinical liver transplantation.

Role of the Immune System: The Major Players
The primary role of the immune response is to protect the individual from invasion by infectious pathogens and to provide self-nonself discrimination. The coordination of an efficient immune response requires the recognition of pathogens and subsequent activation of immune cells and soluble mediators of immunity. The innate immune system, through its ability to rapidly limit the spread of infectious pathogens provides the speed component. In contrast, classical T cells provide the specificity, which requires days to weeks to develop. These discrete subsets function as part of a coordinated and complementary system, and their importance for host defense is seen in secondary responses in which speed and specificity are united in the form of immunological memory.8 Although graft rejection is mediated primarily by T cells, as indicated by the fact that skin grafted onto nude mice, which lack T cells, is not rejected, it is important to understand the division of labor by diverse cells comprising the immune system. Moreover, increasing evidence indicates that T cells also exert regulatory functions, favoring peripheral tolerance.9 Several subsets of CD4 T cells with suppressive properties have been described, including naturally occurring CD4 CD25 regulatory T cells, T regulatory type 1, and T helper (Th) type 3 cells.10 CD4 CD25 regulatory T cells suppress the response of conventional T cells via a cell contact-dependent mechanism, whereas Th3 and T regulatory type 1 cells produce immunosuppressive cytokines, e.g., transforming growth factor- and interleukin (IL)-10. Dendritic cells (DCs) are professional antigen-pre-

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NKT cells expressing the T-cell receptor (TCR) and the invariant V 24J Q TCR. but their expression is dramatically upregulated during maturation in response to appropriate inflammatory stimuli. The ability of DCs to process and present various types of antigens.16 Hepatic suppression of sensitization to antigen absorbed by the portal system was demonstrated as early as 1967.CAQ Corner 371 senting cells (APCs) that are present in virtually all organs and provide a critical link between innate and adaptive immunity.18 Liver sinusoidal endothelial cells (LSECs) have a unique immune phenotype.12 There is expanding evidence that liver-derived DCs can downregulate immune responses. CD11c).20 Golden-Mason and colleagues have documented an unusually high percentage of unconventional lymphoid cells in the liver that are rarely present in the blood. even though recent data suggest that these cells differentiate from hepatocyte progenitors. Evidence for both pathways exists in liver transplantation. For example. as well as dietary and commensal proteins.17 The context in which antigen is presented to T cells determines whether the responding T cell is activated or tolerized. CD4. NK cells possess multiple receptors that can detect conserved antigens or danger signals that mediate MHC-unrestricted cytolysis of susceptible tumor and virus-infected cells. antigen presentation to CD8 T cells by LSECs in vivo leads to their inability to respond to specific antigen upon restimulation.17 In particular. In the direct pathway.17 LSECs resemble immature DCs more than typical microvascular endothelial cells from other organs and seem to be a new type of organ-specific APCs.11 Immature DCs express low levels of major histocompatibility complex (MHC) class II. toxins. In the indirect pathway. including antigens derived from dead cells. CD1d (expressed on the surface of APCs [Kupffer cells] and hepatocytes23) has been shown to be a natural ligand for NKT cells. adhesion. whereas B and T cells possess clonotypic antigen receptors that confer specificity for diverse antigenic structures.25. NK (CD3 CD16 CD56 ) cells represent 5% to 15% of the peripheral mononuclear cell population. and costimulatory molecules. fibrosis development. including NK cells. but in the liver can comprise 45% of the lymphocyte population. thus being able to selectively induce immunity or tolerance to antigens.21. express high levels of immune suppressive IL-10. it has been hypothesized that following liver transplantation. 2). Moreover. hence inducing and maintaining peripheral T-cell tolerance. host T lymphocytes recognize native MHC molecules expressed on graft-associated APCs. This includes the nature of the APC.13 Furthermore.14 The Liver as an Immune Organ Because of its location and function. T cells. these cells play important roles in containment of tumor and viral infections.24 Figure 1 shows the relative proportions of the major lymphocyte subsets present in the healthy adult human liver as compared with the lymphocyte repertoire found in the peripheral blood (used with permission. is unmatched in the human body. Lymphocytes are broadly divided into B cells.22 Although the precise nature of the antigens recognized by these putative regulatory cells is currently unknown.26 It has been suggested that these cells deliver a death signal to circulating recipient derived T cells that migrate through the liver after transplantation.17 CD4 T cells primed by antigen-presenting LSECs fail to differentiate toward effector Th1 cells but. expressing markers typical of cells of myeloid lineage (CD1. the liver is continuously exposed to diverse and large antigenic loads. including pathogens. and tumor cells. from Doherty and O’Farrelly15).15. the adult human liver contains several populations of lymphocytes that exhibit rapid antigen-nonspecific cytotoxicity and regulatory cytokine secretion28.15 The liver must be actively immunocompetent and simultaneously control inappropriate inflammatory responses to dietary and other harmless antigens encountered in the portal circulation.30 It is likely that the direct pathway predominates early posttransplant and is a major factor in acute rejection since graft-derived APCs expressing donor alloan- . hepatic APCs have a constitutive ability to activate and induce tolerogenic responses in T cells. and natural killer (NK) cells. the presence or absence of costimulatory molecules and the cytokine microenvironment.27 Thus. contributing to tolerance. Basic Aspects of T-Cell Recognition of Alloantigen and T-Cell Activation Recipient T lymphocytes can recognize donor alloantigen through either of two pathways. and DCs. instead. these data implicate antigen presentation by LSECs—the only cells to have direct contact with immune cells passing through the liver—as a primary mechanism of systemic tolerance. host T lymphocytes recognize donor alloantigen-derived peptides in the context of self MHC molecules expressed on recipient APCs (Fig.19 Taken together. the existence of large numbers of DCs within the donor liver that circulate and repopulate the recipient contributes to microchimerism.29 and allograft rejection/tolerance.

Thus. B7-1 (CD80). leads to a state of T-cell nonresponsiveness. and macrophages.15) tigen rapidly egress from the graft and enter secondary lymphoid tissue. ligation of CD28 leads to increased production of cytokines such as IL-2. In conjunction with TCR stimulation.32 The indirect pathway probably emanates from donor alloantigen that is shed from damaged graft tissue. or anergy. The .36 CD28 represents the prototypical T-cell costimulatory molecule.31 Host T cells primed through the direct pathway have the ability to engage the allograft directly and. (Adapted from Doherty and O’Farrelly. from soluble MHC class I molecules. the proportion of host T cells that can respond to native alloantigen is substantially greater than the proportion of host T cells that can respond through the indirect pathway to donor-derived peptides presented in the context of self MHC. although CD80 expression is enhanced during APC activation. Two costimulatory molecule-ligand pairs that are important in the generation of a complete T-cell response are CD28/B735 and CD40/CD154. to efficiently mediate effector functions. in which T cells can recognize cognate antigen through the TCR but fail to mount a functional response upon reencounter with the antigen. Indeed. Costimulatory Pathways and Transplantation T lymphocytes must receive two distinct but coordinated signals in order to achieve optimal activation.372 Martinez and Rosen Figure 1. Thus. Further. while the direct pathway may be important in initiating the classical form of acute rejection. and B7-2 (CD86). Distribution of lymphocyte subpopulations in healthy human blood and liver. the indirect pathway may be important in sustaining an ongoing. The first signal is delivered by the TCR following recognition of peptide/MHC complexes on APCs and the second signal is provided by the interaction of costimulatory molecules on the T cells and their cognate ligand/s on APCs. that are picked up and presented by self APCs. cellular proliferation.34 The relative importance of the direct and indirect pathways in liver allograft rejection and tolerance induction remains to be clarified. Signal 1 in the absence of signal 2. The ligands for CD28.production in kidney recipients. CD28 is expressed on 90% of CD4 T cells and 50% of CD8 T cells. persistent response that is fueled by epitope spreading as a variety of allopeptides are successively presented by self APCs. T cells with specificity for allopeptides were readily detected in liver recipients undergoing chronic rejection. The constitutive expression of CD86 is greater than for CD80 on APCs. In humans. are found on a variety of APCs including DCs. as likely occurs in the liver. or perhaps in the case of the liver. there has been significant effort towards inhibiting or blocking costimulation as a means to prolong allograft survival. where they can encounter allospecific T cells. thus.33 At the same time it is possible that the indirect pathway is involved in immune regulation since T cells with allopeptide specificity were shown to have regulatory function through inhibition of interferon (IFN). B cells. and induction of antiapoptotic proteins.

CD8 T cells. monocytes. and DCs. like CD28. Cytotoxic T lymphocyte associated antigen 4 (CTLA4) is a CD28-related protein that is upregulated upon T-cell activation and. Unlike the CD28/B7 costimulatory pathway that has primarily been defined in the context of effects on T-cell function. (A) Pathways of allorecognition. CD86.37 CD86 was found on the majority of Kupffer cells in all transplanted livers and in normal liver. or delayed administration of CTLA4-Ig in combination with donor splenocytes.nature. and CD8 T cells. In the “indirect” pathway. (B) Interactions among endothelial cells. on the other hand. whereas delayed administration of CTLA4-Ig alone or donor splenocytes alone did not. and to a lesser extent on NK cells. CD80 expression did not correlate with the occurrence of acute rejection. T cells recognize processed alloantigen in the form of peptides presented by recipient antigen-presenting cells (right). mast cells. in the graft during severe acute cellular rejection. macrophages. platelets. T cells recognize intact major histocompatibility molecules on donor antigen-presenting cells (left).40 Gene therapy approaches to deliver CTLA4-Ig to liver allografts have been used with some success. Allorecognition pathways and graft rejection. CD80 was instead differentially expressed and was present only sporadically on normal liver but was present on at least 25% of the Kupffer cells in 45% of the transplanted livers. The CD40/CD154 costimulation pathway is a second receptor/ligand pair that is critical in alloimmune responses. including IL-12. used with permission from Nature Publishing Group. The dendritic cells and intragraft macrophages present donor peptides via the indirect pathway to recruited CD4 T cells. CD40 is constitutively expressed on APCs. Recipient monocytes are recruited by endothelial cells to the graft tissue. However. Molecular and immunohistochemical analysis of CD80. lead to extended graft survival of 100 days. CD154 is expressed on CD4 T cells following activation.CAQ Corner 373 Figure 2. but this approach has been hampered by the lack of suitable reagents to deliver the negative signal. are activated by donor endothelial cells and can either directly kill endothelial cells or traverse the endothelium and kill parenchymal graft cells.39 Approaches to inhibit the CD28/B7 and CD40/ CD154 pathways have relied upon specific blocking antibodies or soluble fusion proteins such as CTLA4immunoglobulin (Ig). Whereas CD28 delivers a positive costimulatory signal to T cells. They are also transformed to become highly efficient antigen-presenting dendritic cells that may need to recirculate to peripheral lymphoid organs for maturation. but can also be expressed on nonimmune cells including endothelial cells. In the orthotopic rat liver transplantation model.and T-cell responses to alloantigen. it has been proposed that the physiologic function of CTLA4 is to dampen or downregulate T-cell responses. and because it has a higher affinity for B7 than CD28 does. specific activation of CTLA4 could potentially yield immunoinhibitory function and tolerance induction. In the “direct” pathway. the combination of adeno-associated . CD80. The sum effect of these changes to the APC is to significantly enhance B. (From Briscoe and Sayegh30. and epithelial cells. CTLA4 delivers a negative signal that attenuates T-cell function.38 CD154 was also detected on Kupffer cells and sinusoidal macrophages in livers during chronic rejection but not in stable liver allografts or normal liver. In contrast. CD40/ CD154 ligation augments APC function as measured by upregulation of class II.com) expression of CD80 and CD86 has been examined by immunohistochemistry and real-time polymerase chain reaction in human livers following transplantation. but not CD80. T cells. B cells. repeated administration of CTLA4-Ig beginning at the time of transplantation. Delivery of CTLA4-Ig by adeno-associated virus vectors or low dose FK506 alone failed to induce long-term graft survival. binds to B7-1 and B7-2. and recipient antigen-presenting cells in allograft rejection. and CD154 expression in biopsies of liver recipients demonstrated an association between increased expression of CD86 and CD154. Because CTLA4 expression is enhanced following T-cell activation. including B cells. In contrast. and CD86 expression and production of cytokines. Thus. http://www.

53 A soluble form of CD30 measured in the blood early posttransplantation was shown to be a highly sensitive and specific marker for acute rejection in kidney recipients. respectively. each differentially regulated by Th1 and Th2 cytokines. . they transition to effector cells. CD30 is another T-cell costimulatory molecule that has been implicated in alloimmune responses. although it is now apparent that.55 and this line of investigation will likely expand our understanding of the immune status of graft recipients in the future. The CD40/CD154 pathway was also shown to play a role in ischemia/reperfusion injury. 4-1BB. (2) delayed type hypersensitivity.. characteristic of cellular receptors that deliver a negative signal.46.41 Adenoviralmediated gene delivery of CTLA4-Ig through ex vivo perfusion of cold preserved livers lead to indefinite survival of rat liver allografts and the generation of donorspecific unresponsiveness. independent signaling. PD-1 binds to two ligands. is expressed on activated B cells.and IL-5 producing cells following alloactivation. OX-40/OX-40L (CD134/CD134L). had diminished hepatic injury and neutrophil infiltration in a warm ischemia reperfusion model compared with control mice. mice deficient in PD-1 develop autoimmune-like syndromes. and (3) antibody-mediated damage. The ligand for ICOS. and CD30CD30L(CD153). PDL-1– deficient mice display a spontaneous accumulation of CD8 T cells in the liver. much work has focused on the phenotypic distinction of effector T cells from naıve ¨ cells and memory T cells. Inducible costimulator (ICOS) is expressed following T-cell activation and augments cellular proliferation and cytokine production. there has been considerable interest in two new members of the CD28/B7 family.44 Both treatments lead to prolonged allograft survival but treatment with anti-CD154 was associated with less biliary and endothelial cell injury compared with CTLA4-Ig. Mature effector T cells. Effector Pathways of Graft Injury Once naıve T cells have received signals through the ¨ TCR and the appropriate costimulatory molecules for complete activation.45 Mice deficient in CD154 or wild-type animals treated with anti-CD154. of which CD40/ CD154 are members. ICOS may also participate in development of T regulatory cells. CD30 has been shown to mark the predominant proliferating Tcell population in response to alloantigen52 and CD30 T cells comprise the major population of IFN. shares sequence homology with CTLA4. B7h. T-cell activation lead to an accelerated form of experimental autoimmune hepatitis suggesting that PDL-1 plays a role in the deletion of CD8 T cells in the liver Several members of the tumor necrosis factor/tumor necrosis factor receptor families.50 Interestingly. In contrast. with most animals maintaining their graft over 180 days. Indeed. including the liver. these alternate costimulatory molecules are expressed on T cells relatively late following activation and their relationship to CD28 signaling is still to be determined. are capable of mediating graft injury. The long-standing triumvirate of effector pathways in graft rejection is (1) T-cell–mediated cytotoxicity. in the absence of PDL-1. and DCs. These receptor/ligand pairs include 4-1BB/4-1BBL (CD137). and contains an immunoreceptor tyrosinebased inhibitory motif in the cytoplasmic tail. OX-40 / OX-40L primarily acts on CD4 T cells. macrophages. macrophages and dendritic cells as well as many nonlymphoid tissues. However. ICOS can also trigger the production of the Th1 cytokine IFN. be they CD4 or CD8 .374 Martinez and Rosen virus – CTLA4-Ig transduction and low dose FK506 resulted in long-term graft survival.47 Recently. The receptor 4-1BB is expressed on CD4 and CD8 T cells following activation. The receptor 4-1BB appears to be particularly important in CD8 T-cell responses. there is emerging evidence that other receptor/ligand pairs also play important roles in alloimmune responses.42 Adenoviral-mediated delivery of CD40-Ig fusion proteins also resulted in indefinite rat liver allograft survival and donor specific tolerance. Further.43 The efficacy of anti-CD154 and CTLA4-Ig were compared in a rearterialized rat liver allograft model. Intriguingly. Recently. OX-40.48 The ICOS/B7h pathway was originally thought to provide a costimulatory signal for Th2 cytokine production. programmed death ligand (PDL)-1 and PDL-2. is constitutively expressed on B cells.49 Programmed death-1 (PD-1) is induced upon activation of T cells. PDL-1 is constitutively expressed in the liver on Kupffer cells and sinusoidal endothelium. and any additional cues from cytokines or cell surface receptors required for differentiation. can also provide alternate costimulatory signals to T lymphocytes. while its ligand. 4-1BBL.54 In general. ICOS costimulation plays a central role in T-dependent B-cell activation and isotype switching. While the CD28/B7 and CD40/CD154 costimulatory pathways have garnered the bulk of attention in transplantation. under certain circumstances.51 Moreover. their role in liver transplantation remains to be studied. and CD30 may act to further modulate T-cell function in the context of CD28 signaling or to provide distinct.

alloantibodies directed at MHC class I or class II disparities are not considered to play a prominent role in liver allograft rejection. Suppression of antidonor responses could be broken with antibodies to IL-10 or transforming growth factor. CD4 T cells release IFN. Antibodies specific for graft antigens can mediate graft injury through activation of the complement cascade or through binding to Fc receptors on effector cells and triggering antibody-dependent cell-mediated cytotoxicity. the participation of alternate pathways of graft . the use of the “trans-vivo” assay revealed the presence of active regulatory pathways in 3 patients. Unlike humoral rejection caused by ABO blood group incompatibilities. The presence of donor-sensitized T cells in graft recipients can be revealed in the “trans-vivo” delayed type hypersensitivity response in which peripheral blood mononuclear cells from graft recipients are injected into the ear or footpad of immunodeficient severe combined immunodeficiency mice. CD8 T cells. suggesting that this pathway is operative following human liver transplantation. who had suspended immunosuppression but maintained stable graft function. including 1 liver transplant recipient. peripheral blood mononuclear cells from the 3 patients showed diminished response to donor antigen. it appears that several redundant and compensatory mechanisms are in place that can contribute to graft rejection. Elevations in granzyme B messenger ribonucleic acid are associated with acute liver allograft rejection. It has been a challenging process to try to unravel the participation of specific effector pathways. the antibodies induced expression of CD86 on LSECs and increased T-cell proliferation while decreasing transforming growth factor. Interestingly. macrophages. Delayed type hypersensitivity is initiated by alloantigen-primed CD4 T cells specific for donor class II. Cross-linking of Fas with trimerized FasL or agonist antibodies leads to formation of the death inducing signaling complex in target cells. it was determined that antibodies against LSECs were more frequently observed in patients undergoing rejection than in patients without rejection. Indeed. Whereas FasL is specifically induced upon CTL activation.58. is expressed by CD8 T cells as well as by CD4 T cells and NK cells and can also induce target cell apoptosis. Moreover. concomitant infections.56 In the perforin/granzyme pathway. and their interrelationships. in liver allograft rejection.62 In this study. Further. indicating that these cytokines were essential to maintaining active regulation.59 A more recently characterized molecule. These inflammatory mediators can augment the cellular antigraft response or can cause direct tissue damage. and plasma cells can be found in the liver during rejection.. a proinflammatory cytokine that can cause activation of macrophages and the subsequent release of a variety of soluble mediators. the sensitization status of the recipient. apoptosis is a prominent component of cell death in liver allograft rejection.production in mixed LSEC/T-cell cultures. but good recall responses to unrelated antigens such as Epstein-Barr virus in the “trans-vivo” assay.63 In this study. The Fas/FasL pathway is thought to play an important role in a variety of hepatic pathologies and there is evidence that this pathway is also active during liver allograft rejection.60 However. including the organ transplanted. This ultimately leads to target cell death through apoptosis. Upon reexposure to specific alloantigen. effector cell-derived perforin and the serine protease granzyme B collaborate to induce target cell death.61 The degree of swelling following challenge with specific alloantigen provides an index of prior sensitization. activation of caspase 8. Perforin is inserted into the target cell membrane in a Ca – dependent process forming pores that permit the delivery and entry of granzyme B into the target cell cytosol from preformed cellular granules. Furthermore. and propagation of a death signal that culminates in apoptosis. a significant fraction of the anti-LSEC reactivity was not directed against human leukocyte antigen (HLA) antigens. It is possible to definitively state that CD4 T cells.57 The Fas/Fas ligand (FasL) pathway is another death-inducing pathway utilized by CTL. Rather.. Fas is ubiquitously expressed on lymphoid and nonlymphoid tissue including the liver. a novel mechanism was recently proposed in which antibodies against LSECs indirectly promote acute rejection. it is much more difficult to demonstrate that any of these cell types are actively involved in a destructive immune response. there have been no reports on the involvement of granulysin in liver allograft rejection. Activated CD8 cytotoxic T lymphocytes (CTLs) specific for donor class I can interact with the graft directly and cause tissue injury through biochemical mechanisms that induce apoptosis. granulysin. However.CAQ Corner 375 The relative importance of each of these pathways in graft rejection is likely to depend on a variety of factors. suggesting that other cellular components are the target of these antibodies. The multitude of studies using gene-deficient mice in experimental transplantation models has taught us that it is difficult to definitively identify any single mediator or cell type that is absolutely required for graft rejection. However. and the immunosuppressive protocols that are utilized.

Administration of liver suppressor factor – 1 can prolong rat cardiac allograft survival. which ultimately resolves. can be observed. was cloned from a rejecting liver allograft.69 .59 One candidate cell population that could account for the increase in FasL. NK cells were originally identified on the basis of their ability to kill tumor targets without prior activation or sensitization. have led to a search for mechanisms that account for these findings.66 and it is accompanied by specific increases in messenger ribonucleic acid for perforin. and that liver allografts can even provide “tolerogenic” properties for other organ grants. such as eosinophils. in other studies soluble MHC class I failed to modulate kidney or cardiac allograft survival or inhibit generation of CTL in vivo.71 since an inflammatory infiltrate and early liver injury.77 but elucidation of the mechanism of liver suppressor factor – 1 and the broad applicability of these findings remain to be determined. venous endothelialitis. has been proposed and should be considered as well.76 The finding that serum from rats that spontaneously accept their liver allograft could transfer the protective effect led to a search to identify the suppressive activity. Within the graft. have been difficult to reconcile. with marked inflammatory infiltrates. and parenchymal changes are apparent. Liver suppressor factor – 1 is a 40-kD protein isolated from the serum of spontaneously tolerant recipients (dark Agouti3 Piebald-Viral-Glaxo [PVG]). It has been considered that the large mass of the liver and its regenerative potential could overcome the early injury. as some combinations lead to classic acute cellular rejection. severe acute rejection is underway. As described above. but not isografts. In the rat. apoptosis and graft rejection can occur in the absence of CD8 T cells.74 Direct tests of the effects of soluble class I on graft survival.73 Thus.75 However..65 indicating that rejection is not associated with a polarized Th1 or Th2 cytokine response. Recent studies indicate that large numbers of host NK cells infiltrate liver allografts early posttransplantation68 and express high levels of FasL and granzyme B. tumor necrosis factor. Apoptosis of graft cells is a noted feature of liver allograft rejection. the outcome of liver transplantation is highly dependent upon the particular strain combination used. but this is unlikely to account for the robust protection that the liver affords to subsequent allografts. perforin.64 Experimental Studies on Tolerance in the Liver and Associated Mechanisms A series of experimental and clinical observations indicating that the liver is “less immunogenic” than other vascularized organs. IL-4. bridging necrosis. it has been proposed that soluble donor class I could have immunomodulatory properties through passive blockade of alloantibodies and donor-specific effectors or through induction of activation-induced cell death of allospecific CTL. granzyme B. suggesting that NK cells within the liver have the potential to mediate cytotoxicity. and endothelialitis. rNKp30.72. in the dark Agouti3 Lewis combination. transcripts for IL-2.59. and FasL in allografts. IFN. In some studies. These mechanisms can be divided into 3 categories: soluble factors. a slight mixed and mononuclear cell infiltrate in the portal region and venous endothelialitis are seen by day 2 posttransplantation. Thus. suggesting that these mediators participate in the induction of cell death in the graft. Moreover. with progressive increases through at least day 7. and structural features of the liver. it is reasonable to consider that some active immunoregulatory process is associated with the “liver effect. The strain combinations that result in acute rejection fairly closely recapitulate the features of human liver allograft rejection.. By day 7. cellular components. and granzyme B in rejecting liver allograft are NK cells. whereas others lead to spontaneous tolerance. a novel NK cell activation receptor.59.” Multiple mechanisms have been proposed to explain how the liver could influence or modulate the host immune system. Experimental Studies on Mechanisms of Liver Allograft Rejection The rat orthotopic liver transplant model has been particularly useful in gaining insight into the immunologic mechanisms that are active following liver transplantation. however.65 One day later mononuclear cell infiltration. It is clear from rat and mouse transplantation models of spontaneous liver tolerance that an active immune process of some type is initiated in nonrejecting mouse70 and rat strain combinations.376 Martinez and Rosen rejection by other cell types found within the inflammatory infiltrate. and IL-10 are noted. Almost 20 years ago. direct in vivo administration of rat liver – derived soluble class I prolonged cardiac allograft survival.67 Interestingly. particularly when class I proteins were complexed with anti-class I monoclonal antibodies. Elevations in liver enzymes are measurable in allografts on days 3 to 4. Thus. it was noted that the liver produced and secreted large amounts of soluble MHC class I that could readily be measured in the circulation of healthy individuals and liver recipients.

84 Finally. are exquisitely efficient antigen-presenting cells and are potent inducers of alloreactivity. normal human hepatocytes can produce a soluble form of Fas that is derived from a variant transcript lacking the terminal 5 amino acids of the extracellular region and 16 of 17 amino acids of the transmembrane region. Moreover. unique aspects of the liver’s architecture that allow T cells to come in close contact with tissue cells. suggesting that some cellular component of the graft is responsible. and transfer of the immature DCs to islet allograft recipients prolonged graft survival. Immature DCs.83 Other resident APCs in the liver have also been implicated in liver tolerance. This concept. to persist. When the chimeric liver is retransplanted into the second recipient. although the effect was relatively modest. inactivation of Kupffer cells with gadolinium chloride inhibited tolerance induced via the portal vein route.80 In this model.78 Hepatocyte lysates containing soluble Fas could inhibit anti-Fas – induced apoptosis of Jurkat cells in vitro. progenitor DCs isolated from the liver and propagated in GM-CSF failed to stimulate allogeneic T cells in MLR. not the least of which are differences in the number and type of passenger leukocytes in the various organ grafts and their intrinsic potential for modulating alloimmune responses. While a multitude of studies have implicated liverassociated cells with migratory potential in spontaneous liver tolerance. it has been definitively shown that depletion of resident leukocytes from liver allografts by irradiation markedly diminishes the tolerogenic effect. because donor leukocytes are required for induction of tolerance. Along these lines. In the case of each of these soluble mediators. recovery and retransplantation of a tolerant allograft into a second recipient of the same strain as the first leads to graft rejection rather than tolerance. These data suggest that soluble Fas could modulate the Fas/FasL pathway in liver recipients. As such.14 attributes the tolerogenic properties of the liver to the ability of graft-derived stem cells to migrate out of the graft following transplantation. and because the correlation of microchimerism and graft survival is not absolute. including the LSECs and perhaps hepatocytes. examples of functional immune . spontaneous tolerance does not occur and the graft is rejected. In these studies. the identity of the cell or cells involved has not been solved. and thereby precipitating destructive alloimmune responses. by contrast. however. induces tolerance rather than immunity. were shown many years ago to be required for tolerance induction by the liver. their participation in the “liver effect” in vivo is unclear. Mature DCs. it is possible that they act in concert with other hepatic components to promote tolerance. Support for this model comes from the observation that patients with long-term surviving allografts have evidence of donor cell microchimerism in peripheral tissue. because it has not been feasible to establish whether donor microchimerism in clinical allograft recipients is a cause or an effect of long-term graft survival.81 This disparity between the liver and other organ grafts could be due to multiple factors. However. rich in MHC class II and costimulatory molecule expression.. and may in fact inhibit T-cell responses through incomplete activation. it has been shown that they can inhibit CTL function in vitro. the levels of soluble Fas decreased in patients undergoing graft rejection as compared to patients with a stable course. As already discussed. macrophage-like APCs found in the hepatic sinusoids. do not express significant levels of the costimulatory molecules CD80 and CD86 and as such are poor inducers of Tcell activation. This can be explained by the fact that temporarily “parking” the allogeneic donor liver in the first recipient results in the replacement of the passenger leukocytes with host leukocytes. as discussed previously. a prominent model proposed by Starzl et al. administration of immature DCs to mice did lead to prolonged cardiac allograft survival in the absence of immunosuppression. validation of this model has not been achieved. is in marked contrast to the traditional paradigm of the role of passenger leukocytes in organ allografts in which bone marrow – derived leukocytes associated with the graft are thought to be the critical cell type involved in priming naıve recipient T cells to donor antigens in ¨ secondary lymphoid organs. of course. Indeed. through this process. Finally. and to interact in some fashion with host elements to establish a state of microchimerism that can lead to clonal exhaustion or deletion of host alloreactive T cells.CAQ Corner 377 Finally. could promote T-cell nonresponsiveness or deletion. While it is unlikely that any one of these factors is solely responsible for the tolerogenic properties of liver allografts.79 Similar conclusions can be drawn from studies by Sriwatanawaongsa et al.87 Clearly. LSECs are a unique nonmyeloid APCs found in the liver that can efficiently cross present soluble antigen to CD8 T cells but. thereby creating a chimeric liver.86 demonstrating that Kupffer cells express functional FasL that can induce apoptosis of T cells and that transfer of Kupffer cells derived from accepted grafts can prolong graft survival in an acute rejection model.85 Possible mechanisms for the effect of Kupffer cells in liver tolerance come from recent studies by Sun et al.82 Furthermore. Kupffer cells. One such candidate cell type is the immature DCs found in the liver.

2. Nature 1969. Regulatory T cells in autoimmunity. the immune recognition of the hepatitis C virus – infected allograft may be essential in the containment of infection. Recurrence of Autoimmune Liver Disease. A number of diseases treated by liver transplantation are believed to be autoimmune in origin and. The factors that determine either outcome remain to be determined. TX. and Hepatitis C Virus Recurrence Acute cellular rejection occurs in 50% to 75% of liver allograft recipients and the majority of episodes occur within 90 days of transplant surgery. et al. Davies HS. Sun J. any transplanted organ is as susceptible to the autoimmune process as the organ being replaced. ´ Brousse N. Sakai Y. The induction of transplantation tolerance. Calise D. Effect of liver transplantation on islet allografts: up-regulation of Fas ligand and apoptosis of T lymphocytes are associated with islet graft tolerance. Transplantation 1992. Galveston. 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